CDSCO (INDIA) AND

PHARMACOVIGILANCE
C
HISTORY OF PHARMACOVIGILANCE
IN INDIA
• In 1986, a few physicians, mainly from academic institutions, called for greater
attention to be devoted to the potential adverse effects of prescription
medicines and rational prescribing of medicines.
• This led to formation of the first ADR monitoring program consisting of 12
regional centers, each covering a population of 50 million, but was
unsuccessful.
• Nothing much happened until a decade later when, in 1997, India formally
joined the World Health Organization (WHO) Adverse Drug Reaction
Monitoring Program based in Uppsala, Sweden.
HISTORY OF PHARMACOVIGILANCE
IN INDIA
• Three centers for ADR monitoring were identified, mainly based in the teaching
hospitals: a National Pharmacovigilance Centre located in the Department of
Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi, and two
WHO special centers in Mumbai (KEM Hospital) and Aligarh (JLN Hospital, Aligarh
Muslim University).

• However, they were non-functional, as information about the need to report ADRs
and about the functions of these monitoring centers never reached the
prescribers and there was lack of funding from the government.

• This attempt was also unsuccessful; hence, again from January 1, 2005, the WHO-
sponsored and World Bank-funded National Pharmacovigilance Program (NPVP)
for India was made operational (CDSCO, 2004).
HISTORY OF PHARMACOVIGILANCE
IN INDIA
• The NPVP, established in January 2005, was to be overseen by the National
Pharmacovigilance Advisory Committee based at CDSCO.
• Two zonal centers – the south-west zonal center (located in the Department of
Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai)
and the north-east zonal center (located in the Department of Pharmacology,
AIIMS, New Delhi) – were to collate information from all over the country and
send it to the committee as well as to the Uppsala Monitoring Centre in
Sweden.
• Three regional centers would report to the Mumbai center and two to the New
Delhi one.
HISTORY OF PHARMACOVIGILANCE
IN INDIA
• The program had three broad objectives:
1. the short term objective was to foster a reporting culture,
2. the intermediate objective was to involve a large number of healthcare
professionals in the system in information dissemination, and
3. the long-term objective was for the program to be a benchmark

• However, this program also failed.

THE CURRENT PHARMACOVIGILANCE
PROGRAM IN INDIA
• Recognizing the need to restart the NPVP, in a brainstorming workshop jointly
organized by Department of Pharmacology, AIIMS and CDSCO in late 2009,
the framework of the new and current program was formulated.

• The program now rechristened as the Pharmacovigilance Program for India

(PvPI) was operational from mid July 2010 (CDSCO,).

• This program was coordinated by the Department of Pharmacology at AIIMS

as a National Coordinating Centre (NCC).
PHARMACOVIGILANCE PROGRAM IN
INDIA (PvPI)
• The Central Drugs Standard Control Organization (CDSCO), Directorate
General of Health Services under the aegis of Ministry of Health & Family
Welfare, Government of India in collaboration with Indian Pharmacopeia
commission, Ghaziabad, which acts as a National Coordinating Centre
(NCC), is initiating a nation-wide Pharmacovigilance program for protecting
the health of the patients by assuring drug safety.

• The center will operate under the supervision of a Steering Committee.

PHARMACOVIGILANCE PROGRAM IN
INDIA (PvPI)
Mission:
• Safeguard the health of the Indian population by ensuring that the benefits of
use of medicine outweigh the risks associated with its use.

Vision:
• To improve patient safety and welfare in Indian population by monitoring drug
safety and thereby reducing the risk associated with the use of medicines.
PHARMACOVIGILANCE PROGRAM IN
INDIA (PvPI)
Scope and Objectives:
• To create a nation-wide system for patient safety reporting
• To identify and analyze the new signal (ADR) from the reported cases
• To analyze the benefit-risk ratio of marketed medications
• To generate the evidence based information on safety of medicines
• To support regulatory agencies in the decision-making process on use of
medications
• To communicate the safety information on use of medicines to various
stakeholders to minimize the risk
• To emerge as a national center of excellence for pharmacovigilance activities
• To collaborate with other national centers for the exchange of information
and data management
• To provide training and consultancy support to other national PV centers
located across globe
PHARMACOVIGILANCE PROGRAM IN
INDIA (PvPI)
Short term goals
• To develop and implement pharmacovigilance system in India
• To enroll, initially, all MCI approved medical colleges in the program covering
north, south, east and west of India
• To encourage healthcare professionals in reporting of adverse reaction to
drugs, vaccines, medical devices and biological products
• Collection of case reports and data
PHARMACOVIGILANCE PROGRAM IN
INDIA (PvPI)
Long term goals
• To expand the pharmacovigilance program to all hospitals (govt. & private)
and centers of public health programs located across India
• To develop and implement electronic reporting system (e-reporting)
• To develop reporting culture amongst healthcare professionals
• To make ADR reporting mandatory for healthcare professionals
PHARMACOVIGILANCE PROGRAM IN
INDIA (PvPI)
Communication under PvPI
Effective communication channels are the key to a successful running of
PvPI.
The following chart depicts the movement of information between the
key stakeholders and ensures the continuous transfer of data,
information and knowledge
ROLE OF INDIAN PHARMACEUTICAL
COMPANIES
• In India, a pharmaceutical company holding the marketing license should
ensure that they have an adequate pharmacovigilance system in place to
ensure the responsibility and liability of their marketed products, as specified in
Schedule Y.
• When two or more marketed products are identical in all aspects except their
trade names, each pharmaceutical company holding a marketing license is
obliged to meet the pharmacovigilance obligations.
• This includes establishment and maintenance of appropriate
pharmacovigilance systems to collect, collate, and evaluate information
about suspected adverse reactions.
ROLE OF INDIAN PHARMACEUTICAL
COMPANIES
• All these adverse reaction reports and the information about the benefit–risk
analysis of a product need to be shared with DCGI (Drug Controller General of
India).
• A pharmaceutical company can achieve this either by setting up in-house
systems for pharmacovigilance or can enter into contractual arrangements
with CROs (Contract Research Organizations) specializing in
pharmacovigilance function for meeting their pharmacovigilance obligations.
 DIFFERENCE BETWEEN
INDIAN AND GLOBAL PV
C

REGULATION
GLOBAL SCENARIO
• The global pharmacovigilance scenario is changing both in terms of
regulations and the efforts being undertaken by the regulators,
pharmaceuticals industry, academics, and healthcare professionals.
• Existing regulations are being revised and new regulations are being framed in
several countries.
• However, gaps continue to exist as there is no harmonized regulatory
approach and there are disparities in regulatory requirements that exist in
many countries.
• Interestingly these gaps exist not only between the regulations of the
developed and developing nations, but also within the developed world
GLOBAL SCENARIO
• The introduction of pharmacovigilance regulations in a particular country is
dependent on several factors where the government plays a key decision-
making role.
• The US, EU, and Japan constitute the largest pharmaceutical markets, and
their regulations are some of the most stringent in the world.
• Elsewhere, the emerging markets are increasingly realizing the importance of
pharmacovigilance and of constituting new regulations.
GLOBAL SCENARIO
• Internationally, WHO, through its collaboration with the Uppsala Monitoring
Centre, has created a global network to share data and information about
the benefits and risks of medicinal products.
• This network includes a common database, to which participating members
can contribute medicine safety data, such as ADEs.
• The network membership has grown to include almost 100 countries, including
many developing countries.
FORMULATION OF INDIA’S
PHARMACOVIGILANCE GUIDELINES:
FUTURE PROSPECTS
• Globally, many countries have formulated their own pharmacovigilance
guidelines with the aim to have a systemic process of safety reporting.
• The ICH has six guidelines pertaining to various aspects of drug safety.
• The USFDA has title 21 Code of Federal Regulations (mainly part 312-
Investigational New Drug and part 314-Applications for FDA Approval to
Market a New Drug) and EMEA has entire volume 9A for pharmacovigilance in
humans.
FORMULATION OF INDIA’S
PHARMACOVIGILANCE GUIDELINES:
FUTURE PROSPECTS
• In contrast, India has only a small section of Schedule Y dedicated to drug
safety, which, when viewed in light of contemporary global practice, seems to
have many lacunae.
• It is thus a felt need that CDSCO must formulate a detailed
pharmacovigilance guideline.
• Such a guideline shall incorporate all relevant areas of pre- and post-
marketing safety, address current issues, and bring about clarity in them.
• Most importantly, the guidelines shall be in tune with the current international
norms, so as to support India’s growth in that area.
SCHEDULE Y
C
SCHEDULE Y
REQUIREMENTS AND GUIDELINES FOR PERMISSION
TO IMPORT AND/OR MANUFACTURE OF NEW
DRUGS FOR SALE OR TO UNDERTAKE CLINICAL
TRIALS
APPLICATION FOR PERMISSION
❖Application for permission to import or manufacture new drugs for sale or to undertake
clinical trials shall be made in Form 44 accompanied with following data in
accordance with the appendices, namely:
• Clinical & Pharmaceutical information
• Animal Pharmacology data
• Animal Toxicology data
• Human Clinical Pharmacology data
• Regulatory status in other countries
• Full prescribing information
• Complete testing protocols for QC testing
APPLICATION FOR PERMISSION
❖If the study drug is intended to be imported for the purposes of examination,
test or analysis, the application for import of small quantities of drugs for such
purpose should also be made in Form 12.

❖For drugs indicated in life-threatening/ serious diseases or diseases of special

relevance to the Indian health scenario, the toxicological and clinical data
requirements may be abbreviated, deferred or omitted, as deemed
appropriate by the Licensing authority.
CLINICAL TRIAL
Approval for Clinical Trial
• Clinical trial on a new drug shall be initiated only after the permission has
been granted by the licensing authority and the approval obtained from the
respective ethics committees.
• All trial Investigator(s) should possess appropriate qualifications, training and
experience and should have access to such investigational and treatment
facilities as are relevant to the proposed trial protocol.
• Laboratories used for generating data for clinical trials should be compliant
with Good Laboratory Practices.
• Protocol amendments if become necessary before initiation or during the
course of the trial, all such amendments should be notified to the licensing
authority in writing along with approval by the ethics committee
CLINICAL TRIAL
Responsibilities of Sponsor
• The clinical trial sponsor is responsible for implementing and maintaining
quality assurance systems to ensure that the clinical trial is conducted and
data generated, documented and reported in compliance with the protocol
and GCP guidelines issued by the CDSCO, Directorate General of Health
Services, Govt of India as well as with all applicable statutory provisions.
• SOPs should be documented to ensure compliance with GCP and applicable
regulations.
• Sponsors are required to submit a status report on the clinical trial to the
licensing authority at the prescribed periodicity.
CLINICAL TRIAL
Responsibilities of Sponsor
• In case of studies prematurely discontinued for any reason including lack of
commercial interest in pursuing the new drug application, a summary report
should be submitted within 3 months. The summary report should provide a
brief description of the study, the number of patients exposed to the drug,
dose and duration of exposure, details of ADRs, if any, and the reason for
discontinuation of the study or non-pursuit of the new drug application.
• Any unexpected SAE occurring during a clinical trial should be communicated
promptly (within 14 calendar days) by the sponsor to the licensing authority
and to the other investigators participating in the study.
CLINICAL TRIAL
Responsibilities of the Investigator
• The investigator(s) shall be responsible for the conduct of the trial according to
the protocol and the GCP guidelines and also for compliance as per the
undertaking.
• SOPs are required to be documented by the investigators for the tasks
performed by them.
• During and following a subjects participation in a trial, the investigator should
ensure that adequate medical care is provided to the participant for any
adverse events.
• Investigators shall report all serious and unexpected adverse events to the
sponsor within 24 working hours and to the Ethics committee within 7 working
days of their occurrence.
CLINICAL TRIAL
Informed Consent
• In all trials, a freely given, informed, written consent is required to be obtained
from each study subject. The subject’s consent must be obtained win writing
using an ‘Informed Consent Form’. Both the patient information sheet as well
as the informed consent form should have been approved by the ethics
committee and furnished to the licensing authority.
• Any changes in the informed consent documents should be approved by the
ethics committee and submitted to the licensing authority before such
changes are implemented.
CLINICAL TRIAL
Informed Consent
• Where a subject is not able to give informed consent (e.g. an unconscious
patient or a minor or those suffering from severe mental illness or disability), the
same may be obtained from a legally acceptable representative.
• Is the subject or his/her legally acceptable representative is unable to
read/write- an impartial witness should be present during the entire informed
consent process who must append his/her signatures to the consent form.
• A checklist of essential elements to be included in the study subject’s Informed
Consent Form for study subjects is given in Appendix V.
CLINICAL TRIAL
Responsibilities of the Ethics Committee
• Ethics committee should safeguard the rights, safety and well-being of trial
subjects
• Ethics committee should make, at appropriate intervals, an ongoing review of
the trials. Such a review may be based on the periodic study progress reports
furnished by the investigators and/or monitoring and internal audit reports
furnished by the Sponsor and/or by visiting the study sites.
• In case an ethics committee revokes its approval accorded to a trial protocol,
it must record the reasons for doing so and at once communicate such a
decision to the Investigator as well as to the Licensing Authority.
CLINICAL TRIAL
Human Pharmacology (Phase I)
• The objective of studies in this phase is the estimation of safety and tolerability
with the initial administration of an investigational new drug into humans.
• Studies conducted in phase I, usually intend to involve one or a combination
of the following objectives:
a. Maximum tolerated dose
b. Pharmacokinetics
c. Pharmacodynamics
d. Early measurement of drug activity
CLINICAL TRIAL
Therapeutic Exploratory Trials (Phase II)
• The primary objective of Phase II trials is to evaluate the effectiveness of a drug
for a particular indication or indications in patients with the condition under
study and to determine the common short term side effects and risks
associated with the drug.
• An important goal for this phase is to determine the doses and regimen for
Phase III trials.
• Additional objectives of Phase II studies can include evaluation of potential
study end points, therapeutic regimens (including concomitant medications)
and target populations for further studies in Phase III.
CLINICAL TRIAL
Therapeutic Confirmatory Trials (Phase III)
• Phase III studies have primary objective of demonstration or confirmation of
therapeutic benefits.
• Studies in Phase III are designed to confirm the preliminary evidence
accumulated in Phase II that a drug is safe and effective for use in the
intended indication and recipient population
• For drugs approved outside India, Phase III studies need to be carried out
primarily to generate evidence of efficacy and safety of the drug in Indian
patients when used as recommended in the prescribing information.
CLINICAL TRIAL
Post Marketing Trials (Phase IV)
• Post Marketing Trials are studies performed after drug approval and related to
the approved indications.
• These trials go beyond the prior demonstration of the drug’s safety, efficacy
and dose definition.
• These trials are required by the licensing authority for optimizing the drug’s use.
• Phase IV trials include additional drug-drug interactions, dose-response or
safety studies and trials designed to support use under the approved
indications, e.g. mortality/morbidity studies, epidemiological studies, etc.
STUDIES IN SPECIAL POPULATIONS
Information supporting the use of the drug in children, pregnant women, nursing
women, elderly patients, patients with renal or other organ systems failure, and
those on specific concomitant medication is required to be submitted if
relevant to the clinical profile of the drug and its anticipated usage pattern.
POST MARKETING SURVEILLANCE
Subsequent to approval of the product, new drugs should be closely monitored
for their clinical safety once they are marketed.
The applicants shall furnish PSURs in order to:
• Report all the relevant new information from appropriate sources
• Relate these data to patient exposure
• Summarize the market authorization status in different countries and any
significant variations related to safety
• Indicate whether changes should be made to product information in order to
optimize the use of the product.
POST MARKETING SURVEILLANCE
Ordinarily all dosage forms and formulations as well as indications for new drugs
should be covered in one PSUR.
The PSURs shall be submitted every 6 months for the first 2 years after approval of
the drug is granted to the applicant.
For subsequent two years, the PSURs need to be submitted annually.
PSURs due for a period must be submitted within 30 calendar days of the last
day of the reporting period.
However, all cases involving serious unexpected adverse reactions must be
reported to the licensing authority within 15 days of initial receipt of the
information.
New studies specifically planned or conducted to examine a safety issue should
be described in the PSURs.
POST MARKETING SURVEILLANCE
A PSUR should be structured as follows:
• A title page
• Introduction
• Current worldwide market authorization status
• Update of actions taken for safety reasons
• Changes to reference safety information
• Estimated patient exposure
• Presentation of individual case histories
• Other information
• Overall safety evaluation
• Conclusion
• Appendix
 APPENDICES
APPENDIX NO. DESCRIPTION
I Data to be submitted along with the application to conduct clinical trials/ import/
manufacture of new drugs for marketing in the country
IA Data required to be submitted by an applicant for grant of permission to import
and/or manufacture a new drug already approved in the country
II Structure, contents and format for clinical study reports
III Animal toxicology (non-clinical toxicity studies)
IV Animal pharmacology
V Informed consent
VI Fixed dose combinations (FDCs)
VII Undertaking by the investigator
VIII Ethics committee
IX Stability testing of new drugs
X Contents of the proposed protocol for conducting clinical trials
XI Data elements for reporting serious adverse events occurring in a clinical trial
APPENDIX XI: Data Elements for reporting
SAE occurring in a Clinical Trial
Sr. No. Data Elements Sub-elements
1 Patient Details Initials and other relevant identifier, Gender, Age and/or
DOB, Weight, Height
2 Suspected Drug(s) Generic name of the drug, Indications, Dosage form and
strength, Daily dose and regimen, Route of administration,
Starting date and time, Duration of treatment
3 Other treatments Same information for concomitant drugs as for suspected
drugs
4 Details of Full description of reactions including body site and
Suspected ADRs severity, Start date (and time), Stop date (and time),
Setting
5 Outcome Information on recovery, results of specific tests and/or
treatment.
For a fatal outcome, cause of death, any post-mortem
findings
APPENDIX XI: Data Elements for reporting
SAE occurring in a Clinical Trial
Sr. No. Data Elements Sub-elements
6 Details about the Name
Investigator Address, telephone number,
Profession (Speciality)
Date of reporting the event to Licensing authority
Date of reporting the event to Ethics Committee
Signature of the Investigator